The long term goal is to understand estrogen's role in learning and memory, in hippocampal neuron function, in synaptogenesis, and how the malfunction of these is relevant to human diseases. Clinical study reveals that estrogen treatment affects women~s spatial tasks, verbal memory, and fine motor skills, and improves the mental status of female Alzheimer~s patients. Parallel study in rat also demonstrated estrogens impact on cognitive functions. Furthermore, at the cellular level, it has been shown that estrogen induces dendritic spines and new synapses in the hippocampal neurons. Hence, it is imperative to understand the molecular mechanisms of the estrogen induced synaptogenesis in hippocampal neurons, because: a) synaptogenesis is one of the most fundamental neuronal activities and a critical cellular basis for learning and memory; and b) hippocampus is an essential brain region that accounts for many learning and memory tasks. The specific aim of this proposed study is to identify molecular components and mechanisms of this process. A hippocampal cell culture system has been developed, in which synaptogenesis can be induced by estrogen treatment. Utilizing this system, a)molecules known to be important in synaptogenesis, such as cAMP responsive element binding protein (CREB), protein phosphotase I (PPI) and NMDA receptor will be examined for their changes in transcription, translation and phosphorylation, with or without estrogen induction; b) a hypothesis of the pathway will be tested; c)mRNA differential display technique will be used to identify new molecules that are induced or suppressed in estrogen induced synaptogenesis.